title: A novel succinyl dipeptide stimulates directed cell migration by modulating protein kinase C activity.
abstract: In determining the mechanism of the chemokinetic action of the thiol protease inhibitor, E-64, in endothelial cell monolayers subjected to wounding, we synthesized succinyl-leucyl-agmatine (SLA), an analogue of E-64 that lacked the epoxy group and protease inhibitory effect. We observed that this analogue retained its chemokinetic effect on wounded endothelial cells. Its stimulatory action on endothelial cell polarization response to wounding was rapid and associated with directed cell migration. Furthermore, its effect on cellular polarization was blocked by protein kinase C (PKC) inhibitors and mimicked by pharmacologic agents that stimulated PKC activity. To determine if SLA's chemokinetic action was mediated by protein kinase C activation, we compared the effects of SLA and the tumor promoter phorbol myristate acetate (PMA) on the translocation of PKC activity in endothelial cells. We observed that both SLA and PMA induced the translocation of PKC activity from the cytosolic to the particulate fraction of the cells. We also observed that both SLA and PMA induced the phosphorylation of two proteins (Mr 23.4 and 36.5 kDa) in intact 32P-labeled cells. Thus, SLA stimulates the endothelial cell locomotor response to wounding by stimulating PKC activity.
authors.affiliation: Department of Medicine, Danbury Hospital, Connecticut 06810.
authors.forename: R N
authors.initials: RN
authors.lastname: Mascardo
authors.forename: W
authors.initials: W
authors.lastname: Thompson
authors.forename: M A
authors.initials: MA
authors.lastname: Gallo
authors.forename: T C
authors.initials: TC
authors.lastname: Chambers
authors.forename: G
authors.initials: G
authors.lastname: Eilon
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D002460:Cell Line; D002630:Chemotactic Factors / Q000494:pharmacology*; D002633:Chemotaxis; D004151:Dipeptides / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D008969:Molecular Sequence Data; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D013386:Succinates / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D002630:Chemotactic Factors; D004151:Dipeptides; D010750:Phosphoproteins; D013386:Succinates; C062992:succinyl-leucyl-agmatine; D009240:N-Formylmethionine Leucyl-Phenylalanine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate